Ketolides, a well-known family of antimicrobial agents, are semisynthetic 14-membered ring macrolide derivatives, characterized by the presence of a keto function at position 3 instead of L-cladinose moiety present in the macrolactone ring. Telithromycin and Cethromycin are examples of ketolides.
Telithromycin is described in U.S. Pat. No. 5,635,485 and Bioorg. Med. Chem. Lett. 1999, 9(21), 3075-3080. Another ketolide Cethromycin (ABT 773) and other are disclosed in PCT application No. WO 98/09978, and J. Med. Chem. 2000, 43, 1045.
The U.S. Pat. No. 6,900,183 describes 11,12-ylactone ketolides having C-21 of the lactone substituted with cyano or amino derivatives. The patent applications such as U.S. 2004/0077557 and PCT publications WO 02/16380, WO 03/42228, WO 03/072588 and WO 04/16634 disclose 11,12-γ lactone ketolides. Our co-pending PCT application No. WO 08/023248 discloses several Macrolides and Ketolides.
The ketolide compounds of the invention bearing a thiadiazole heteroaryl in the side chain are useful antimicrobial agent. The compounds of invention have shown unexpectedly superior potency against the Gram-positive bacteria including the macrolide and ketolide resistant strains. Remarkebly, compounds of the invention are characterized by superior oral effectiveness in the treatment of resistant microbial infections.